Annually malaria afflicts an estimated 200 to 300 million people and results in 2 million deaths worldwide. Malaria is a protozoan infection of the blood and liver resulting from the introduction of the parasite into the bloodstream of the individual via the bite of an infected anopheles mosquito, transfusion of infected blood, or injection with a contaminated needle. The life cycle of the malaria parasite includes stages of maturation in liver cells and multiplication/asexual reproduction in the red blood cells. The induced rupture of the red blood cells when the progeny are released and the occlusion of blood vessels due to the parasitized red blood cells may result in symptoms ranging from low-grade fever, chills, headache, malaise and myalgia to severe headache, drowsiness, delerium and acute attacks of fever and chills and may be fatal if left untreated.
Chloroquine, 7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline, was introduced for the prevention and treatment of malaria over 40 years ago and is currently the most widely used drug in the prophylaxis and treatment of malaria. Though chloroquine is effective against three of the four plasmodium species that cause malaria, certain strains of Plasmodium falciparum which are resistant to chloroquine, 4-aminoquinolines and quinolines, in general, have developed in geographic regions where malaria is endemic.
The resistance of these plasmodia is possibly due to a decreased accumulation of chloroquine in the parasite resulting from the rapid efflux of the drug from the resistant parasite. This removal of chloroquine occurs via a putative chloroquine efflux pump, inhibition of which would provide a useful method for allowing accumulation of the antimalarial agent and hence prompting a reversal of the chemical resistance of the parasite.
Chloroquine resistance in Plasmodia falciparum shares some of the characteristics of multidrug resistance found in mammalian tumor cells (Nature, 340 342 (1989), Cell, 57, 921-930 (1989)). It is known that some compounds which reverse multidrug resistance in mammalian tumor cells may also act to reverse chloroquine resistance in P. falciparum (Science, 235, 899, (1987)). In addition some calcium channel blockers including verapamil and diltiazem inhibit the removal of chloroquine from the plasmodia and reverse chloroquine resistance in vitro and/or in vivo (Science, 238, 1283, (1987)). Desipramine and several tricyclic antidepressant compounds also have the ability to reverse chloroquine resistance and may be useful in combinative therapy with chloroquine in patients infected with chloroquine resistant plasmodium species (Science, 242, 1301 (1988)). These antidepressants, in particular desipramine, suffer from the problem that potentially harmful dosages are required to induce remission of chloroquine resistance.
At present, the most preferred method of prophylaxis for chloroquine resistant P. falciparum which involves administration of a combination of chloroquine with pyrimethamine and sulfadoxine suffers from the possibility of inducing severe cutaneous reactions in the patient. Likewise, the current treatment for drug-resistant falciparum malaria which involves the concurrent administration of quinine, pyrimethamine, and a sulfonamide (such as sulfadiazine) may result in side effects including tinnitus, drug fever, allergic purpara, and anemia. There remains, therefore, a very real and substantial need for an adjunct therapy to chloroquine administration in the prophylaxis and treatment of chloroquine resistant P. falciparum that minimizes potential side effects.
The compounds of this invention being tricyclic compounds are effective in combination with chloroquine for the prophlaxis, suppression therapy, and treatment of chloroquine resistant P. falciparum. In addition, the compounds of this invention exhibit a synergistic effect with chloroquine and, hence, are useful in combination therapy against chloroquine resistant malaria parasites.
The present invention has met the above described need by providing a method which preferably involves administering to a person a therapeutically effective dosage of the compound of this invention in combination with or concurrent with the administration of a therapeutically effective dosage of an antimalarial drug either as a prophylaxis for or as direct treatment of drug-resistant malarials. In addition, the compounds of this invention may have a lower propensity to induce extrapyramidal side effects that are experienced with many tricyclic compounds.